The present invention is concerned with improved antiinflammatory salts of piroxicam treating inflammation therewith. These salts are composed of piroxicam in 1:1 molar ratio with antidepressant doxepin, bronchodilator pirbuterol or isoproterenol, histamine-H.sub.2 antagonist 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, with pyridoxine or another member of the vitamin B.sub.6 complex such as pyridoxal or pyridoxamine, or with antihypertensive trimazosin or structurally related antihypertensive compound. The generic names used here and elsewhere herein are from the USAN and the USP Dictionary of Drug Names, 1961-1981, Griffiths et al., ed., U.S. Pharmacopeial Convention Inc., Rockville, Md., 1984, have subsequently been assigned and published as official USAN names, and/or appear in The Merck Index 10th Edition. Alternative chemical names which are provided in The Merck Index are listed below.
Gastrointestinal irritation, including ulcers, is a side effect commonly associated, to one degree or another, with antiinflammatory agents. In many cases, individuals requiring such antiinflammatory treatment are precluded from enjoying the benefits thereof because of their susceptibility to such side effects. The present salts of piroxicam with one or another medicinal agent, as defined above, permit desirable antiinflammatory therapy while preventing or ameliorating said gastrointestinal irritation or ulcers.
Bronchodilators salbutamol (albuterol), phenylephrine and isoproterenol, but not propranolol, have been reported to inhibit formation of indomethacin-induced ulcers in animals [Fielding et al., Eur. Surg. Res. 9, 252 (1977); Kasuya et al., Japan J. Pharmacol. 29, 670 (1979)]. In another study, administration of isoproterenol to a chambered section of a dog's fundus reduced or prevented aspirin-induced tissue damage [McGreevy et al., Surg. Forum 28, 357 (1977)]. There are no known prior reports concerning the effect of bronchodilator pirbuterol on antiinflammatory agents.
Antidepressant doxepin has also been reported to have gastric antisecretory activity and to be as effective as cimetidine in the treatment of duodenal ulcers in humans [Hoff et al., Curr. Med. Res. Opin. vol. 6, supplement 9, page 36 (1980); Scand. J. Gastroent. 16, 1041 (1981)]. It has also been reported that doxepin shows antiulcer and antisecretory activity in rats and dogs; and that it significantly reduced the ulcerogenic potential of indomethacin, diclofenac and aspirin in water-immersion restraint-stressed rats [Leitold et al. Arch. Pharmacol. 316 (supplement), R50, abstract 199 (1981); Leitold et al., Advances in Experimental Ulcer, Umehara and Ito, editors, ICEU, Tokyo pp. 27-36 (1982); Arzneim-Forsch/Drug Res. 34, 468 (1984).
Histamine-H.sub.2 antagonist (gastric acid antisecretory, antiulcer) compounds such as ranitidine, cimetidine and 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propylamino]]-1H-1,2,4-tria zole-3-methanol have been previously physically combined with indomethacin, piroxicam and other antiinflammatory agents to decrease gastric irritation. See, for example, U.K. patent application Nos. 2,105,193 and 2,105,588; and Lovelace, U.S. Pat. No. 4,230,717.
There are no known literature reports concerning the use of an antihypertensive agent such as trimazosin, a vitamin such as pyridoxine or a minor tranquilizer such as diazepam in reducing gastric side-effects induced by nonsteroidal antiinflammatory agents.
Concurrently filed U.S. patent application Ser. No. 659,602 by Crawford et al. describes the combination of piroxicam (or a pharmaceutically-acceptable salt) with either doxepin, trimazosin, pyridoxine or pirbuterol (or their pharmaceutically-acceptable salts) in improved antiinflammatory compositions and methods. Concurrently filed U.S. patent application Ser. No. 659,752 by LaMattina describes such a combination of piroxicam with 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole.